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Imaging Biomarker Roadmap for Cancer John.Waterton@Manchester.Ac.Uk Imaging Biomarkers in Radiation Oncology and Beyond: Development, Evaluation and Clinical Translation Imaging Biomarker Roadmap for Cancer [email protected] AAPM/COMP 2020-07-14 Funding Support, Disclosures, and Conflict of Interest statement FUNDING. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement number 115151, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007- 2013) and EFPIA companies’ in kind contribution. Part of the work was also performed during the author's previous employment with AstraZeneca, a for-profit company engaged in the discovery, development, manufacturing and marketing of proprietary therapeutics. DISCLOSURES & CONFLICT OF INTEREST. John Waterton holds stock in Quantitative Imaging Ltd and receives compensation from Bioxydyn Ltd, a for-profit company engaged in the discovery, development, provision and marketing of imaging biomarkers. BEST resource (2016) Biomarker: A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. Molecular, histologic, radiographic, or physiologic characteristics are types of biomarkers. A biomarker is not an assessment of how an individual feels, functions, or survives. Categories of biomarkers include: • susceptibility/risk biomarker • diagnostic biomarker • monitoring biomarker • prognostic biomarker • predictive biomarker Development of 1999 workshop • pharmacodynamic/response biomarker (Atkinson et al 2001) • safety biomarker Six key cancer imaging modalities Metrology Colloquial Examples definition definition Ordered How ugly? categorical (incl. binary) Extensive How big? Intensive How hot? Metrology Colloquial Examples definition definition Ordered How ugly? • TNM stage PET SPECT vis XR/CT MR us categorical • OR PET SPECT vis XR/CT MR us (incl. binary) • ACR BIRADS breast morphology XR • 99mTc-etarfolatide FR+ SPECT • Radiomic signature of heterogeneity CT Extensive How big? • LVEF SPECT MR us • Spleen volume CT MR • circumferential resection margin in rectal cancer MR 111 Intensive How hot? • SUVmax In-pentetreotide SPECT 18 PET • SUVmax F-fludeoxyglucose • Aprepitant receptor occupancy % PET • ΔKtrans gadoterate MR • DCE-US AUC us • MRI ADC MR 13 • C-pyruvate kp MR Problem statement: imaging biomarkers in cancer • Not a new idea – predates molecular biology! • Tumour size: 1940s/50s • Tumor T1 (1971) led to invention of MRI • Exemplified in FDA/NIH biomarker workshop (1999) • Today used routinely – all BEST categories • Cancer drug development • Regulatory approval • Routine oncologic practice • Many investigational imaging biomarkers in cancer • Disappointing rate of translation – why? “…molecular, histologic, radiographic, or physiologic characteristics…” Biospecimen removed from patient Biosignal measured in vivo molecule or cell analyte detected with in vitro Diagnostic Device signals detected by in vivo Diagnostic Device biofluids urine imaging genetics blood electromagnetic soluble biomarkers exhalate fields & photons electrophysiology sputum PET saliva physiologic measurement immunohistochemistry SPECT semen CT, XR in situ hybridisation faeces wearables/smartphones synovial fluid endoscopy genomics CSF fluorescence etc etc MRI/S proteomics ECG EEG metabolomics MEG cytology solid tissues etc cervical smear sound & pressure microbiology skin biopsy ultrasound hair follicle infrasound erythrocyte sedimentation buccal biopsy palpation etc liver biopsy auscultation bone biopsy plethysmography synovial biopsy spirometry tumour biopsy etc excised tumour etc Imaging biomarker: Biospecimen biomarker: Scanner in hospital Radiology Dept In vitro diagnostic device Different scanners from different vendors Identical IVDDs installed in different hospitals Scanners not designed, maintained or IVDDs designed, maintained and approved for measuring biomarkers approved for specific measurement Main job role not quantitation Trained, dedicated staff Quality depends mainly on events at the Quality depends mainly on the moment of scanning central lab Picture quality drives innovation: Stable platform due to regulatory unpredictable effect on quantitation approval Seldom defined analytes Defined molecular entity via analytical biochemistry Typical biospecimen biomarker validation roadmap Molecule of biological interest (“analyte”) Biospecimen Assay development Assay validation Clinical validation Clinical utility roadmap Nature Reviews Clinical Oncology 14:169-186 (2017) http://dx.doi.org/10.1038/nrclinonc.2016.162 Includes supplementary files • Problem statement • Examples – all modalities and contexts of use • Definitions • Detailed roadmap • Recommendations Figure 2 The imaging biomarker roadmap O’Connor, J. P. B. et al. (2016) Imaging biomarker roadmap for cancer studies Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2016.162 Figure 1 Overview of the imaging biomarker roadmap O’Connor, J. P. B. et al. (2016) Imaging biomarker roadmap for cancer studies Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2016.162 Key perspectives Imaging (biosignal) bm Typical biospecimen bm Technical validation, clinical validation, Iterative in parallel Mainly in series clinical utility Biological validation Biological and clinical Definitive clinical outcome platform of evidence validity studies e.g. Kaplan Meier e.g. Bradford Hill criteria Roadmap recommendations 1. Align grants and publications to roadmap 2. Exhaustively document methodology in publications 3-7. Technical (assay validation) Consensus, accreditation, repeatability, reproducibility, analysis methodology 8-11. Biological and clinical validation Platform of evidence (Bradford Hill criteria) Imaging-pathology correlation (human and aniumal) Data sharing Publication bias 12. Design of outcome studies 13-14. Cost effectiveness and clinical utility Imaging agents pricing; QALY advantage The problem of poorly aligned incentives Standardisation not considered innovative by funding agencies nor career-enhancing for academics Novel biomarker can’t be used without reliable accurate measurement. Not a good use of vendors’ Can’t acquire evidence base resources to provide accurate unless scanners routinely measurement unless demand generate accurate from customers (radiologists) measurements Radiologists won’t demand accurate measurements without evidence from multicentre trials to show impact of measurement on health outcomes. Innovative approaches to incentivisation Incentivisation through public-private partnerships, professional bodies • Standardising FDG-PET, FLT-PET, MRI-ADC, MRI-Ktrans, MRI-DIILD etc Academics innovate, businesses standardise questions.
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